Project Summary/Abstract There is a fundamental gap in understanding the effect of local delivery of antibiotics for the prevention and treatment of peri-prosthetic joint infections, a truly morbid and costly complication threatening >1 million patients undergoing joint arthroplasty each year. There is currently no fully load-bearing medical device which can also be used for the controlled release of antibiotics to treat peri-prosthetic joint infection (PJI). The current standard of treatment (there is none for prevention) involves a two-stage revision during which patients are immobilized for more than 3 months. Available treatments are effective only about 40-80% of the time with recurrence increasing morbidity, mortality and cost tremendously. There is a great need to improve outcomes, patients? quality of life and to reduce cost. Our long-term goal is to develop materials and methods to enable and thoughtfully control the local release of therapeutics to treat orthopaedic conditions. The overall objective of this application is to devise an antibiotic- eluting and load-bearing joint implant platform technology and its implementation strategy to improve the treatment of PJI. Our central hypothesis is that by manipulating the synergy of incorporated drugs, drug/polymer interactions and drug incorporation methods, an ultrahigh molecular weight polyethylene (UHMWPE) implant with optimal antibiotic efficiency and safety can be designed. The rationale for the proposed research is that by using a newly discovered antibiotic synergy between local PJI antibiotics and commonly used analgesics, we can optimize drug elution profiles with maximum efficacy in preventing the growth of clinically relevant infections of variable risk. This strategy has the potential of changing the treatment paradigms for improved outcomes without any additional risks to patients. The specific aims are (1) identifying the factors in engineering UHMWPE with synergistic antibacterial release and (2) developing preclinical risk- stratification tests for the implementation of antibiotic-eluting UHMWPE. The challenge of developing a tough, fully load-bearing and wear resistant surface while incorporating drugs in the polymer will be overcome by two strategies: introducing highly eccentric drug clusters that enable lower drug loading and spatially limiting the drug-loaded regions to low load bearing regions of the implant. The approach is innovative firstly because it departs from the current methods of depending on antibiotic elution from temporary, non-weight bearing bone cement devices often assembled in the operating room and secondly because analgesics, which can improve the efficacy of antibiotics, can be delivered concurrently at a predetermined rate using this device. The expected outcome is a platform bearing surface technology and an implementation strategy tailored to the infecting microorganism. The strategies capitalize on the team?s expertise in the development of clinically used UHMWPE implants based on innovations in antioxidant stabilization, cross-linking and morphology manipulation. We present strong preliminary data showing the feasibility of our ideas including incorporating vancomycin in UHMWPE with safe and efficient release in pre-clinical planktonic and biofilm infection models and the synergy between the analgesic drugs ketorolac and bupivacaine with gentamicin. The proposed research is significant, because it is expected to provide a new, safe and efficient implant for combating PJI, which can eliminate the costly and burdensome gold standard of two-stage revision with temporary immobilization.